15 Biopsies des côtes (mois 6)Remodelage intra-cortical et porosité Modèle de singe cynomolgus ovariectomiséeSHAM ControlOVX ControlOVX + 25 mg/kg DmabOVX + 50 mg/kg DmabBiopsies des côtes (mois 6)210160**110/yr)260m*Haversian BFR / BSm/103^^m**m3^(^*2*^^1**Mois 6Mois 12DiaphyseTibiaSHAM-VehOVX-VehBiopsies des côtes5Moyenne ± SE*P< 0.05 vs. OVX-Veh^P< 0.05 vs. Sham-Veh4Denosumab also reduced intracortical bone formation rate to levels below OVX and sham controls, resulting in significantly lower cortical porosity.The 6-month rib biopsy images demonstrate the increase in cortical porosity and haversian bone formation with ovariectomy, which were reduced by denosumabIt is interesting to note the rapid increase in cortical porosity in rib biopsies within 6 months of OVX. While cortical remodeling has been suggested to be related to the deliberate repair of microdamage, it is hard to imagine from these data that such “targeted” remodeling is a substantial component of the overall cortical remodeling response. These are ~10 year old animals that had years to repair any existing microdamage, and yet there is a marked increase in intracortical remodeling within 6 months of ovariectomy. It seems more likely that this intracortical remodeling response is a metabolically-driven process resulting from estrogen ablation.3**Cortical Porosity (%)**2^*^^^***125mg/kgDmab50mg/kgDmabMois 6Mois 12DiaphyseTibiaBiopsies des côtesOminsky MS, et al. J Bone Miner Res. 2006;21(suppl 1):S72 ;

16 Product Blue Template_Logo_SMS_v1b.PPTGain osseux cortical sous Denosumab lié à des modifications de l’aire corticale et de la vBMD Modèle de singe cynomolgus ovariectomiséeRadial Cortical Area3691215-4-3-2-11*^Months of Treatment% Change from BaselineTibial Cortical Area3691215-10-8-6-4-22*^Months of TreatmentSHAM ControlOVX ControlOVX + 25 mg/kg DMABOVX + 50 mg/kg DMABpQCT Tibial DiaphysisRadial Cortical vBMD3691215-5-4-3-2-11*^Months of Treatment% Change from BaselineTibial Cortical vBMD3691215-6-5-4-3-2-112*^Months of TreatmentThe decreases in cortical bone mass can be broken down into loss of cortical area and loss of cortical BMD (BMC = Area*BMD).Here we see that ovariectomy led to decreases in both cortical area and BMD at both sites.The loss of BMC in the sham group appeared to be primarily due to loss of cortical area and not BMD (which would reflect a change in intracortical turnover).Finally, denosumab led to slight (1-2%) increases from baseline in both cortical area and BMD by study’s end.Data: Mean ± SE*P< 0.05 vs. OVX-Veh^P< 0.05 vs. Sham-VehOminsky et al. J Bone Miner Res 2007 (Suppl 1) abstract 108216

36 Denosumab et risque de nouvelles fractures vertébrales année par année Phase 3: FREEDOM – Etude pivot anti-fracturaire78% P < 0.00165% P < 0.001Placebo3,5%Denosumab3,0%3,1%3,1%61% P < 0.0012,5%2,0%2,2%Incidence (%)1,5%1,0%1,1%0,9%At month 36 of the study, treatment with 60 mg of denosumab every six months significantly reduced the risk of new vertebral fractures by 68% versus placebo (2.3% denosumab versus 7.2% placebo; P < 0.001).1The FREEDOM trial was designed with > 99% power to detect a 45% reduction in the incidence of new vertebral fractures.1Statistical analysis was based on the assumption of 4% per year vertebral fracture rate in the placebo group.1The last known fracture status of patients who were lost to follow-up or withdrew before having a fracture event was carried forward in the analysis.1The reduction in risk was similar during each year of the trial, 61%, 78%, and 65% for years 1–3, respectively.1Similar reductions were observed for1:New clinical vertebral fractures, with a 69% reduction over 3 years (P < 0.001)Multiple new vertebral fractures, with a 61% reduction over 3 years (P < 0.001)A central imaging center was utilized to assess annual lateral spine radiographs for new vertebral fractures based on a semiquantitative grading scale.1The criteria for a new vertebral fracture was an increase of at least one grade in a vertebral body that was normal at baseline.1All fractures diagnosed based on clinical symptoms were confirmed by radiographs.1Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med Aug 20;361(8):0,5%0,7%0,0%Année 1Année 2Année 3Analyse en Intention de TraitementLe pourcentage de nouvelles fractures vertébrales a été calculé sur la base du nombre de patientes avec une radiographie rachis à l’inclusion et au moins un examen après.Adapté de Cummings SR, et al. N Engl J Med Aug 20;361(8):756-653636

47 Variation vs baseline (%)Prévention de perte osseuse au radius: os trabéculaire et cortical Modèle de singe cynomolgus ovariectomiséeSham-VehOVX-VehOVX-25 mg/kg denosumabOVX-50 mg/kg denosumabDMO (1/3 distal du radius)vBMC total (métaphyse du radius)vBMC cortical (diaphyse du radius)555*^***^*^*^Variation vs baseline (%)–5–5–5*–10–10–10Denosumab prevented loss of both trabecular and cortical bone at the radius in aged OVX monkeys.1As shown in the left graph, at month 16, areal BMD at the distal third of the radius was significantly greater in aged OVX cynomolgus monkeys treated with denosumab (25 and 50 mg/kg) compared with OVX-V monkeys (P < 0.05).1As shown in the middle graph, at month 16, total volumetric BMC of the radial metaphysis was significantly greater in aged OVX cynomolgus monkeys treated with denosumab (25 and 50 mg/kg) compared with OVX-V and sham-V monkeys (P < 0.05).1As shown in the right graph, at month 16, cortical volumetric BMC of the radial diaphysis was significantly greater in aged OVX cynomolgus monkeys treated with denosumab (25 and 50 mg/kg) compared with OVX-V and sham-V monkeys (P < 0.05).1This hypothesis has not been proven in humans.Potential Question: Why did animals in the sham groups lose bone during the study?Answer: The negative changes in densitometry were not consistent across all endpoints. The majority of apparent bone loss at certain endpoints appeared to occur during the first 4 months after sham surgery. This suggests there may have been changes caused by the sham surgery, increased animal handling, or animal stress during acclimation. The animals used in this study were considered to be “semi-feral” which means they had been caught within the past year. Although the animals were acclimatized for 2 months, their frequent change in diet, combined with multiple visits to the animal facility may have left them in a higher turnover state than normal. In fact, biomarkers of bone turnover decreased over the course of the 16-month study after month 3.Changes in densitometric measures in sham-operated monkeys are not unusual; gains or losses in spine BMD have been reported in similar studies.2,3Ominsky MS, et al. J Bone Miner Res. 2006;21(suppl 1):S72. Abstract 1272 and presentation.Brommage R. J Musculoskel Neuro Inter. 2001;1(4):Jerome CP, Peterson PE. Bone. 2001;29(1):1-6.–15–15–15Après 16 mois de traitementDMO: reflète la densité minérale osseuse surfacique mesurée par un scanner DEXAvBMC: reflète le contenu minéral osseux par unité de volume mesurée par pQCTn = 14–20/groupe.*P < 0.05 vs OVX-V; ^P < 0.05 vs sham-V.Ominsky MS, et al. J Bone Miner Res. 2006;21(suppl 1):S72. Abstract 1272 et oral.

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